This invention relates to a process for brominating aromatic compounds, particularly thiophene compounds. More specifically, this invention relates to a process for selectively brominating the alkyl side-chain of 3-alkyl thiophenes.
Thiophenes have considerable interest as intermediates for pharmaceutical compounds, particularly amino acid antagonists, in vasopressor action and intermediates for antibacterial semisynthetic penicillin and cephalosporin compounds, particularly Ticarcillin.
In view of such interest, any number of methods have been described in the chemical literature for the preparation of brominated aromatic compounds. Particularly, brominated alkyl thiophenes, described in Campaigne et al, J. Amer. Chem. Soc., Vol. 70, pp. 1555-1558 (1948), are prepared by reacting 3-methylthiophene with N-bromosuccinimide in the presence of a benzoyl peroxide initiator. The 3-thenyl bromide was subsequently used for preparation of other thiophene compounds. Selectivity of reaction on the methyl side-chain was much increased by the use of benzoyl peroxide as an initiator. Dittmer et al, J. Amer. Chem. Soc., Vol. 71, pp. 1201-1204 (1949), teaches that excess brominating agent, such as 2 moles of N-bromosuccinimide per mole of 2- or 3-methylthiophene will give dibrominated thiophenes even in the presence of a directing benzoyl peroxide initiator. One mole of brominating agent per mole of 2- or 3-methylthiophene gives predominately side-chain brominated methylthiophene in the presence of benzoyl peroxide initiator. The preparation of 3-thenyl bromide from 3-methylthiophene using benzoyl peroxide initiator and N-bromosuccinimide brominating agent is also taught in Organic Syntheses, Vol. 33, pp. 96-98 (1953). The use of various activators or initiators for the N-bromosuccinimide brominating agent is taught in Horner et al, Newer Methods of Preparative Organic Chemistry, Vol. III, Academic Press, New York, New York (1964), pp. 151-168. Peroxides and azobisisobutyronitrile as free radical initiators were discussed for the reaction producing brominated thiophenes. The article teaches that photoinitiation is unfavorable and particularly shows the effect of ultraviolet light which, although operative, is considerably less reactive and selective. Offermann et al, Synthesis, 272 (1977) teach brominating each methyl side-chain of 2,6-dimethylpyridine in the presence of light and an azobisisobutyronitrile initiator.
The recent advances in pharmaceutical uses for thiophene compounds as chemical intermediates and as building blocks in pharmaceutical compounds indicates a need for processes which will produce such intermediates without serious waste disposal problems, at reasonable cost and with as few undesirable by-products as possible. Such undesirable by-products produced by non-selective bromination processes cause impurity problems in the final intermediate and require extensive waste purification with the attendant problems of excessive cost of processing and equipment. Further, it is always desired to increase the productivity of given reaction equipment by increasing the yield, which also lowers the cost of such valuable pharmaceutical intermediates. It is particularly desired to increase the selectivity of the reaction for alkylating the side-chains, especially the lower alkyl side-chains, of heterocyclic compounds such as thiophenes. Accordingly, a process having the advantages described above would be extremely desirable. The process provided by the present invention realizes such advantages.